RARE Daily

Intellia Presents Preclinical Proof of Concept for CRISPR-Based in Vivo Editing

March 11, 2021

Rare Daily Staff

Intellia Therapeutics said it presented preclinical data that provides a proof-of-concept for non-viral genome editing of bone marrow and hematopoietic stem cells in mice, a first demonstration of systemic in vivo genome editing in tissue outside the liver using its proprietary non-viral delivery platform.

Gene editing of hematopoietic stem cells (HSCs) in vivo via a non-viral delivery system offers the potential to transform the treatment of sickle cell disease (SCD) and other inherited blood disorders by overcoming the complexity and safety risks of ex vivo approaches.

Sickle cell disease is caused by a mutation in the beta globin gene that leads to sickling of red blood cells and clotting in small arteries. The disease is characterized by severe pain and multi-organ injury, including in the brain, heart, lungs, kidneys and joints, with greatly reduced life expectancy and quality of life. Standard of care therapies include hydroxyurea and frequent RBC transfusions from healthy donors. Allogenic hematopoietic stem cell transplantation is reserved as a last resort for severely affected patients, though is limited by associated morbidities, high cost, and the need for specialized clinical care, and is generally not accessible to patients in countries with limited healthcare resources.

The company said an in vivo gene editing strategy, in which CRISPR/Cas9 is delivered systemically as a treatment into patients, could greatly reduce the risk, cost, and barriers to treatment associated with ex vivo genomic modification of HSCs. Such an approach could provide a one-time, curative treatment option for patients worldwide who are suffering from SCD. The company presented the data at the Keystone eSymposium: Precision Engineering of the Genome, Epigenome and Transcriptome, which was held virtually.

While CRISPR/Cas9-based genome editing is well suited to the treatment of hereditary blood disorders, such as SCD, the requirement for ex vivo manipulation of HSCs and toxic myeloablative transplantation regimens are significant barriers to widespread adoption of this approach.

Intellia’s non-viral delivery platform enables systemic administration of CRISPR/Cas9 to disease-relevant tissues through the use of lipid nanoparticles (LNPs). The study showed the LNPs enabled transient and well-tolerated delivery of CRISPR/Cas9 to murine and human hematopoietic stem and progenitor cells in mice.

Dose-dependent editing was seen in whole bone marrow as well as HSPCs, with editing levels in hematopoietic stem cells found to be durable for more than one year after a single LNP administration.

The scientists found that editing increased upon repeat LNP administration, which opens the potential for a “treat-to-target” approach.

Intellia is currently building upon this preclinical work, towards a potential cure for SCD, with a grant from the Bill & Melinda Gates Foundation.

“This new data supports the possibility of delivering a safer solution to treat blood disorders, including sickle cell disease, by avoiding the need for bone marrow transplantation,” said John Leonard, president and CEO of Intellia. “We’ve demonstrated we can expand our in vivo capabilities originally designed for liver applications to other tissues and achieve therapeutically meaningful levels of gene editing, reinforcing the promise of Intellia’s modular platform to transform the lives of people living with genetic diseases.”

Photo: John Leonard, president and CEO of Intellia


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